Gene expression profiling of laminin α3‐blocked keratinocytes reveals an immune‐independent mechanism of blistering

Abstract

Laminin-332 pemphigoid, a subset of mucous membrane pemphigoid (MMP), is a rare and chronic, autoimmune blistering disease which results in subepidermal blisters and erosive lesions predominantly localized to mucous membranes. 1 The pathogenesis involves IgG autoantibodies against laminin-332 in the basement membrane zone (BMZ). 1 While typically clinically indistinguishable from other forms of mucous membrane pemphigoid, laminin-332 pemphigoid appears to predispose to more aggressive laryngopharyngeal involvement. [2][3][4][5] Complications from laminin-332 include scarring, which can lead to blindness or strictures along the oral-gastrointestinal and urogenital and tracts. 3,4 Laminin-332 is an extracellular glycoprotein and a vital component of the BMZ. It is a heterotrimer composed of the domains α3, β3 and γ2 with a large G domain at the base containing epidermal growth factor-based repeats. 6,7 While laminin α3 is the most frequently targeted domain in laminin-332 pemphigoid, patients often express varying amounts of β3 and γ2 antibodies. 5,8 The unique cross-shaped structure of laminin-332 and its various C-terminal

Anti‐α6β4 integrin autoantibodies inhibit the binding of laminins to α6β4 integrin in patients with pemphigoid and affect the gastrointestinal tract

“…Inhibition of laminin-332-α6β4integrin binding has been reported to affect keratinocyte differentiation and induce blister formation. 33,34 α6β4 integrin-inhibiting antibodies may cause blistering by a similar mechanism. At least the patient's serum contained antibodies that inhibited the α6β4 integrin binding to both laminin-332 and laminin-511, which may have caused cutaneous and systemic symptoms.…”

“…However, in addition to inhibition of laminin‐332‐α6β4 integrin binding, inhibition of laminin‐511‐α6β4 integrin binding by the anti‐α6β4 integrin antibodies, as shown here, may be pathogenic in vivo . Inhibition of laminin‐332‐α6β4integrin binding has been reported to affect keratinocyte differentiation and induce blister formation 33,34 . α6β4 integrin‐inhibiting antibodies may cause blistering by a similar mechanism.…”

Dupilumab effectively and rapidly treats bullous pemphigoid by inhibiting the activities of multiple cell types

“…The complement-dependent pathway is initiated by antigenantibody complexes in the basement membrane zone; these complexes activate complement (36-39). The complementindependent pathway is induced principally by antibodies and eosinophils, which results in blister formation regardless of complement activation (4,13,(40)(41)(42)(43). Plasma proteome profiling before and after dupilumab treatment revealed 26down-regulated proteins, such as ICOSL/B7H2, PRG2, S100A12, and CD21/CR2, which involved in T/B cell and B cell/complement interactions, eosinophil degranulation, and mast cell activation (44)(45)(46)(47).…”

Adaptive and innate immune pathogenesis of bullous pemphigoid: A review

“…Antigen–IgG4 induced the separation of the BMZ through a complement-independent pathway ( 5 , 22 , 134 ). The antigen–antibody combination leads to the recruitment of neutrophils and eosinophils in BP, and, consequently, to the release of proteolytic enzymes ( 5 ).…”